Susceptibility gene for familial acute myeloid leukemia associated with loss of 5q and/or 7q is not localized on the commonly deleted portion of 5q

Genes Chromosomes Cancer. 2000 Jun;28(2):164-72.


The molecular mechanism for the occurrence of leukemia in multiple members of a family has not been fully elucidated but data support the contribution of highly penetrant mutations in leukemia susceptibility genes. We have investigated the genetic etiology of an unusual three-generation family with apparent autosomal dominant transmission of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) accompanied by somatic loss of the long arm of chromosome 5 and/or loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) of leukemia cells have been performed, confirming acquired hemi- and homozygous deletion of the long arm of chromosome 5. However, the chromosome lost in the observed LOH event is from the affected parent, in contradiction to the expectation for a two-hit hypothesis involving a tumor suppressor gene. Furthermore, genetic linkage has been performed at 5q31-33 as well as other loci (21q22 and 16q21-23.2) previously implicated in familial leukemia. In this family, linkage analysis excludes loci at 5q31-33 and 21q22, but localization to 16q21-23.2 cannot be excluded. We observed a maximum multipoint LOD score of 1.19 between marker D16S265 and D16S503 at 16q22 (P = 0.03), suggesting possible linkage to this locus. Considering this family and the previous 16q-linked family together, the linkage of a leukemia susceptibility gene to 16q22 achieved an LOD score of 3.63 at D16S265 with theta = 0. Thus, somatic deletion of the long arm of chromosome 5 appears as a necessary but surprisingly noncausative event for onset of AML and MDS in this family, thereby confirming a multistep etiology in which chromosome 5 plays an important secondary role.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Adult
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 16 / genetics
  • Chromosomes, Human, Pair 5 / genetics*
  • Chromosomes, Human, Pair 5 / metabolism*
  • Chromosomes, Human, Pair 7 / genetics*
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Karyotyping
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / pathology*
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Pedigree